Project Summary/Abstract Accumulating evidence shows that traumatic brain injury (TBI) impairs the ability to restore homeostasis in response to a stressor, reflecting dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis. As a result, normal everyday stressors elicit intense ?wear and tear? or ?allostatic load? on the body and substantially influence outcome after brain injury. The overall hypothesis is that daily sleep disruption is a physiologically relevant stressor that directly engages the HPA-axis after TBI, and upon a dysregulated stress response promotes increased neuroinflammation, neuropathology, and behavioral impairment. Published data show that microglia are ?primed? after TBI and become hyper-reactive in response to secondary immune challenge resulting in increased neuropathology and behavioral impairment. Since reactive microglia can drive neuronal injury and the spreading of progressive neurodegeneration through the brain, preliminary data suggest that they are the primary effector cells that exacerbate neuroinflammation and pathology after post-injury sleep disruption. Three specific aims will test the following hypotheses: (Aim 1) TBI reduces the corticosterone (CORT)-mediated neuroendocrine response to sleep disruption resulting in worsened neuropathology and recovery; (Aim 2) TBI mice demonstrate increased glucocorticoid negative-feedback sensitivity and restoration of the CORT response to sleep disruption will reduce neuroinflammation and neuropathology; (Aim 3) Post-TBI sleep disruption will enhance tau pathology and behavioral impairments caused by TBI, which will both be improved upon pharmacological removal of microglia. Upon conclusion, sleep disruption can be considered a post-injury stressor that challenges the HPA-axis and mediates increased post-injury neuroinflammation through glucocorticoid receptors. The therapeutic potential of removing microglia to improve outcome following post-injury sleep disruption will also be confirmed. The proposed research is innovative because, for the first time data are provided to show that sleep disruption can serve as a pathological stressor that exacerbates neuroinflammation, neuropathology, and behavioral impairment after TBI. These studies can prompt the development of therapeutic interventions that do not require drug development. For example, specific guidelines can be implemented to reduce nighttime awakenings in hospitals and care facilities. The ultimate goal of this proposal is to highlight the neuroendocrine effects of post-injury sleep disruption and identify key molecular pathways that promote chronic neuroinflammation and neurodegeneration after TBI.